The purpose of this proposal is to test the overall hypothesis that allelic variation in a gene(s) causes a change in its function rendering it a hypertension or atherosclerosis -causing or -susceptibility gene, and that defined manipulation of the mouse genome can be used to test the physiological significance of genetic variants in human genes, and its interaction with environmental and genetic stressors. The studies proposed herein will provide mechanistic studies on the biological consequences of variations in the NOS3 (eNOS) and SOD3 (ecSOD) genes and on the interaction of genetic and non-genetic factors that modulate the susceptibility to disease. We propose to examine two common allelic or haplotypic variants of each gene by generating mouse models in which identical genes differing only at the variant positions are specifically targeted to the mouse genome in a way, which will allow direct comparison among genetic variants. In each case we will compare the effects of allelic variation on baseline blood pressure, vascular function and the genesis of atherosclerosis. Moreover, the contribution of each allelic variant on vascular function, hypertension and atherogenesis will be compared in mice induced to be hypertensive either genetically or experimentally, in mice induced to become atherosclerotic, and in mice under environmental stressors such as a high sodium diet, high fat diet or with other risk factors such as obesity and atherosclerosis. To accomplish this goal we will: 1) Generate "knockin" mice in which each gene variant is specifically targeted in a single copy to a single defined locus in the mouse genome, and where appropriate breed each gene variant to a genetic background deficient in endogenous mouse gene of interest, 2) Compare baseline blood pressure, vascular function, and atherogenesis in each set of allelic models, 3) Compare blood pressure, vascular function and atherogenesis in mice made genetically or experimentally hypertensive, in mice made genetically atherosclerotic or obese or challenged by other CVD risk factors such as a high salt or high fat diet. These aims will allow us to assess the physiological importance of allelic variation in six genes implicated as risk factors in the pathogenesis of human essential hypertension or atherosclerosis.